1-carbobenzoxy-4-substituted piperazines



Patented Nov. 11, 1952 rest ()FFICE l-CARBOBENZOXY- l-SUBSTITUTED 1PIPEBAZINES Leon Goldman, River Edge, N. J., assignor toAinericancyanainid Company, New York, N. Y., a corporation'of Maine NoDrawing. Application March 21, 1951, Serial No. 216,851

7 Claims. (Cl. 260-268) This invention relates to new organic compoundsand their preparation. More particularly, it relates to1-carbobenzoxy-4-substituted piperaz'ines.

The 1-carbobenzoxypiperazines of the present invention may beillustrated by the following general formua': v

in which R is a member of the group consisting of hydrogen and loweralkyl radicals, R is a member of the group consisting of hydrogen;alkyl, aryl, cycloalkyl and aralkyl radicals and X is a member of thegroup consisting of oxygen, sulfur and imino radicals. As used hereinthe term lower alkyl radical means a radical of 1 to 4 carbon atoms.

In general the compounds of the present invention are colorlesscrystalline solids. The compounds are, in general, slightly soluble inwater but are readily soluble in benzene, lower aliphatic alcohols,chloroform and the like. In the general formula when X is an iminoradical water soluble addition salts may be formed.

The new compounds of the present invention may be prepared in severalways, the most desirable method being dependent to a large extent on thenature'of the produce desired. In general, I prefer to prepare thecompounds byreacting a l-carbobenzoxypiperazine having the formula:

with any compound which is capable of introducing into the it-positionof the piperazine nucleus a group represented by X R t s R! in which R,R and-X are as nereinbefore defined. The l-carbobenzoiiypiperazine is anew compound and a method for its preparation is given in the exampleshereinafter. The acid salts of the 1- 'carbobenzoxypiperazine canobviously be used as starting material. In a reaction of this typewherein a halogen acid is liberated it is usually desirable tohave-present an acid binding substance such as an alkali metalbicarbonate, alkali metal carbonate, alkali "metal hydroxide or similaralkaline substance or an excess or the i-car bobenzoxypiperazine,

' primary or secondary amine.

The intermediates to be reacted with the 1- carbobenzoxypiperazine oracid salt thereof can be an alkali metal cyanate or a mono ordialkylcarbamyl halide or a 'nitrourea to produce thelcarbobenzoXy-4-carbamyl piperazines. In producing1-carbobenzoxy-4-thiocarbamyl piperaai'nes I can use an alkali metalthiocyanate, an aliphatic isothiocyanate or a mono ordialkylthiocarbamyl chloride. The guanyl derivatives of 1-carbobenzoxypiperazine may be prepared by the reaction of a1carbobenzoxypiperazine salt with a cyanamide or they can also beprepared by reacting l-carbobenzoxypiperazine an S-alkyl isothioureasalt. These latter reactions can be carried out in a solvent such as anaqueous lower aliphatic alcohol.

The process of the present invention; in general is preferably carriedout in a solvent although it can be carried out without a solvent whereat least one of the intermediates are liquid. Temperatures of 5 to 100C. are usually sufiicient to complete the reaction in a reasonablelength of time when water is used as the solvent. Generally the reactionis carried out at 20 C. to about C.

when aqueous alcoholic solvents are hydrocarbon solvents, such asbenzene, are used. The specific conditions under which the reaction iscarried out are dependent upon the group being introduced into the4-position and also upon the reactivity of the 1-carbobenzoxypiperazine.For instance, l-carbobenzoxypiper'az'ine hydrochloride can be reacted inaqueous solution with potassium cyanate at room temperature or below togive l-carbobenzoxy 4 carbamylpiperazine.

However, when reacting l-carbobenzoxypiperazine withphehylacethydroxamic acid benzoate in aqueous solution it is desirableto heat the reaction mixture at steam bath temperatures in order tocomplete the reaction.

In general, all of the compounds in which X of the general formula isoxygen may be prepared by another method such as reactingl-carbobenzoxy-4-chl orocarbonylpiperazine' with ammonia, a As illustrat'diin the general formula, these primary or seco dary amines may becompounds such as methylamine, dimethylamine, aniline,cyclohexyla'min'e, benzylamine, etc. The l-carbobenz xyl-chlorocarbamylpiper'azine is a new compound and its preparation is described in theenainples which follow.

A still further method an preparing the 1-Carbobenz'oxyl-monosubstituted carbamyl piperazine is the reaction ofl-carbobenaoxypiperazine with an aryl or alkyl isocyanate.

The compounds of the present invention generally possess marked activityas anticonvulsants, and may be useful for other purposes. In general,the compounds are characterized by their relatively low toxicity.

The following examples show in greater particularity the preparation ofa number of l-carbobenzoxy-e-substituted piperazines within the scope ofthe present invention.

EXAMPLE 1 1 -carbobenzoficy--carbamylpiperazine A mixture of 97 g. ofpiperazine hexahydrate in 750 m1. of methanol and 95 ml. of water wasacidified to pH 3.5, in the presence of bromphenol blue, with 155 ml. of6N hydrochloric acid. The resulting solution was stirred and 95 g. of a90% solution of carbobenzoxy chloride in toluene and 220 ml. of 4Nsodium hydroxide were added at rates which maintained the pH near 4.6;the final pH was 5.5. The resulting mixture was slowly brought toreflux, refluxed hour, and let stand. overnight. The methanol wasremoved under reduced pressure, the residual liquid was made a1- kalinewith sodium hydroxide, anhydrous sodium carbonate was added, and themixture extracted with 200 ml. and 2x100 ml. of chloroform. Thechloroform extract was extracted with 250 ml. of dilute hydrochloricacid, and the chloroform extract was washed with water. The chloroformextracts were concentrated to dryness under reduced pressure, andcrystallization of the residue from ethanol-ethyl acetate gave 9.0 g. oflA-dicarbobenzoxypiperazine, M. P. 109-112 C. When recrystallized fromabsolute ethanol colorless crystals were obtained having a melting point112.0-113.0 C.

The acid aqueous extract was made alkaline with sodium hydroxide, andthe oil which separated was extracted with 4X50 ml. of chloroform. Thechloroform extract was dried over anhydrous potassium carbonate, andthen distilled under reduced pressure. The l-carbobenzoxypiperazinedistilled as a colorless liquid, B. P. 140-150/1 mm. (mainly atlee-146); yield 50.9 g. (46% of the theoretical amount).

A mixture of 34 g. of 1-carbobenzoxypiperazine prepared above and 17.9g. of nitrourea in 200 ml. of water was heated on a steam bath. After 15minutes gas evolution had ceased and an oil separated. On cooling, theoil solidified to a colorless solid which was removed by filtration andair-dried. The yield of l-carbobenzoxylcarbamylpiperazine was 35.4 g.(85% of the theoretical amount). When crystallized from ethanol,colorless shiny plates were obtained, melting point 140.'7-14l.5 0.

EXAMPLE 2 1-carbobenzoxy-a -carbamylpiperazine 1 liter of water. Theresulting solution was removed from the ice bath and within minutescolorless crystals formed. After four and one half hours the suspensionwas chilled, filtered, washed with iced water and dried, yielding 260 g.(89% of the theoretical amount). Qf, 1.- arb n- 4zoxy-e-carbamylpiperazine, melting point 138.5 l39.5 C. (sinters 137.50.).

EXAMPLE 3 1 -carbobenzoscy-el-methylcarb amylpipcrazme Under anhydrousconditions, a solution of 112.6 g. (0.512 mole) ofl-carbobenzoxypiperazine in 100 ml. of dry benzene was added to astirred, chilled solution of 29.8 g. (0.302 mole) of phosgene in 150 ml.of dry toluene during the course of 1 hour. After stirring at 0 for ll/hours the precipitate was removed by filtration. The combined filtrateand washings was distilled under reduced pressure and thel-carbobenzoxy-echlorocarbonylpiperazine distilled as a colorlessliquid, undergoing a little decomposition, at 203 208/1.3-1.5 mm.

To 50 m1. of a 25% aqueous solution of methylamine and excess ice wasadded, while stirring, a benzene-toluene solution of 0.12 mole ofl-carbobenzoxy 4 chlorocarbonylpiperazine. After one hour the reactionmixture was concentrated under reduced pressure to remove the excessmethylamine, benzene and toluene. The residue, consisting of an oil andan aqueous solution, was acidified with a small amount of hydrochloricacid and on cooling the oil solidified. The solid was removed byfiltration, washed with water and dried at 100 0., yielding 29.8 g. ofthe theoretical amount) of l-carbobenzoxy-emethylcarbamylpiperazine.When crystallized from ethyl acetate, colorless crystals were obtained,melting point 120.0120.5 C.

EXAMPLE 4 1 -carbobeneoxy-4-dimethylcarbamylpiperaeine A solution of10.8 g. of dimethylcarbamyl chloride in 10 ml. of ethyl acetate wasadded, with stirring and cooling, to a chilled solution of 44 g. of1-carbobenzoxypiperazine in 250 ml. of ethyl acetate. After one-halfhour at 0 C., the reaction mixture was allowed to stand at roomtemperature overnight. The precipitate was removed by filtration, washedwith ethyl acetate and dried, yielding 21.5 g. of colorless crystals ofl-carbobenzoxypiperazine hydrochloride. The filtrate was concentrated ona steam bath and the residual yellow oil was dissolved in chloroform,washed with N hydrochloric acid, 5% sodium bicarbonate and water anddried over anhydrous magnesium sulfate. The chloroform solution wasdistilled under reduced pressure and after the chloroform was removedthe 1-carbobenzoxy-4-dimethylcarbamylpiperazine distilled as a viscouscolorless liquid, boiling point 206-20'7/1.1 mm., 16.1 g. (55% of thetheoretical amount).

EXAMPLE 5 1-carbobenzoccy-4-ethylcarbamylpiperaeinc A solution of 0.11mole of l-carbobenzoxy-ichlorocarbonylpiperazine in toluene was added toa stirred mixture of 25 ml. of 33% aqueous ethylamine and ice. Afterstirring 2 hours, the colorless crystals were removed by filtration,washed with iced water and dried at C., yielding 22.3 g. of1-carbobenzoxy-4-ethylcarbamylpiperazine, melting point -123 C.Concentration of the filtrate gave an additional 6.6 g., bringing thetotal yield to 28.9 g. (90% of the theoretical amount).Recrystallization from ethyl acetate and from aqueous ethanol gavecolorless crystals, melting point 126.0-126.5 C.

aer'neoa 1 -earhobenzo:c-y-4 n-propylt:arbamylpiperaaine To a coldmixture of 207 g. of a toluene solution of 0.236moleof-1-carbobenzoxy-4-chlcro carbonylpiperazineand 100 ml. of ethylacetate was added dropwise, with agitation, 32.3 g. of n-propyla-mine:On filtration, crystals were ob tained which'were -triturated=withdi1ute acid-and washed with water, yielding 43.3 g: of colorlesscrystalsof" I-carbobenzoxy-4-n-propylcarbamyb piperazine; Concentrationof the mother liquor gavea solidwhich when crystallized from ethylacetate, tr-iturated" withdilute acid and washed with water, yieldedan'additional 28.8 g.- of product: Recrystallization from ethyl acetateyield ed colorless crystals, melting point 112.5 1-1'3-.5-' C.

EXAMPLE 7 1 -carb o benzoxy-4-isopropylcarbamylpip erazz'ne Reaction of.0.122 mole, of, l-carbobenzoxy-4- chlorocarbonylpiperazine with-0.294mole. of isopropylamine according to the procedureof Ex ample-Gylelded37.8 g. of crude l-carbobenzoxy- 4-isopropylcarbamylpiperazine. Whenrecrystallized. from ethyl, acetate and from 50% ethanol, colorlesscrystals were obtained, meltin point 118-119- C.

EXAMPLE 8.

1 -carbobcneoa1y-4-n-butylcarbamylpipemeine To an iced solution of- 89g. of a toluene solution of 0.1 mole of1-carbobenzoxy-4-chlorocarbonylpiperazine in 250 m1. of ethyl acetate,18.3 g. of n-butylamine. was added in small portions, with shaking.After standing at room temperature' overnight, 11.2 g. of n -butylaminehydrochloride was obtained by filtration and washing with ethyl.acetate. The filtrate was concentrated to dryness and crystallizationfrom ethyl acetate and petroleum ether gave 34.1 g. of crudel-carbobenzoxy 4 n-butylcarbamylpiperazine. Recrystallization from ethylacetate, 50% ethanol and ethyl acetate-ether gave colorless crystals,melting point 94.095.5 C.

EXAMPLE 9 1 -carbobcnzorzr-4-sec-butylc-arbamylpiperazinc Reaction of0.1 mole of l-carbobenzoxy-4- chlorocarbonylpiperazine with 0.25 mole ofsecbutylamine according to the procedure of Example 8 gave 11.4 g. ofcrystals of sec-butylamine hydrochloride and 29.1 g. of crudel-carbobenzoxy-4-sec-butyl-carbamylpiper-azine. Recrystallization fromether gave colorless crystals, melting point 58-59 C.

EXAMPLE l0 1 -carb'obenzory-4mhenylcarbamylpipemzine A solution of 11.9g. (0.1 mole) of phenyl isocyanate in 20 ml. of benzene was added,dropwise, to a stirred, chilled solution of 22 g. (0.1 mole) ofl-ca-rbobenzoxypiperazine in 100 ml. of benzene. The mixture wasrefluxed for one hour, cooled and the resulting colorless crystalsremoved by filtration, washed with benzene, and dried. The yield ofl-carbobenzoxy-4-phenylcarbamylpiperazine was 32.3 g. (95% of thetheoretical amount). When recrystallized from benzene and absoluteethanol, colorless crystals were obtained, melting point 139.5-140.0 C.

1.2-caretbenzcxu r12hcny carbcmylr remame A mixture of 41.7 g; of atoluene solution of 0.1 mole; of1-carbobenzoxy-l-chlorocarbonylpiperazine, 9.3 g: (0.11 mole)of'aniline, and 25 ml. of 4N sodium hydroxide was shaken in a stopperedflaslrfor 22 hours. The reaction mixture was then acidified withhydrochloric acid and the aqueous layer was decanted. Theorganiclayerwas diluted with 20-40 ligroin and the colorless crystals were removedby filtration, washed with 20-40 ligroin, washed with, water andair-dried. The yield of l-carbobenzoxy-4-phenylcarbamyl piperazine was27.2 g. of the theoretical amount)... Recrystallization from. absoluteetham]; and benzene gave, colorless crystals, melting point 139 140 C.

bearbobenaoscw4*0-cmorophenylcarbamyle piperazz'ne A solution of 15.4 g.(0.1 mole) of o-chlorophenyl' isocyanate in 25 ml. of benzene was addedto acold solution of- 22 g. (0.1 mole) of l-carbobenzoxypiperazinein100' ml. ofbenzene and the resulting solution, which slowly depositedcrys tals, was allowed to stand at room temperature overnight. Thecolorless crystals were removed by-filtration and air-dried. The yieldof l-carbobenzoxy- 4 -'o-chlorophenylcarbamylpiperazine was 35.4 g. ofthe theoretical amount). When recrystallized from benzene and absoluteethanol, colorless crystals were obtained, melting point 118.5-119.5 C.

EXAMPLE 13 1-carbobenzory-4 -p-phenetylcarbamylpipemaine A solution of16.3 g; (0.1 mole) of p-phene'tyl' isocyanate in 25 ml. of benzene wasadded to a solution of 22 g. (0.1 mole) of l-carbobenzoxypiperazine inml. of benzene. After 4 hours at room temperature the suspension washeatedto boiling and then cooled. The colorless crystals were removed byfiltration and air-dried. The yield ofl-carbobenzoxy-4--p-phenetylcarbamylpiperazine was 29 g. (76% of thetheortical amount). The product was recrystallized from absoluteethanol, yielding colorless crystals, melting point l47.0-148.0 C.

EXAMPLE l4 1 -carbcbenzomy-4-m-tolylcarbamylpipemzine A solution of 13.3g. (0.1 mole) of m-tolyl isocyanate in 25 ml. of benzene was added to asolution of 22 g. (0.1 mole) of l-carbobenzoxypiperazine in 100 ml. ofbenzene, with cooling. After 3 days at room temperature, the mixture washeated to boiling, filtered to remove a small amount of precipitate andconcentrated under reduced pressure to dryness. The yield of colorlessl-carbobenzoxy 4 m tolylcarbamylpiper- Mine was 34.8 g. (99% of thetheoretical amount). When recrystallized from absolute ethanol,colorless crystals were obtained, melting point 136.0136.5 C.

EXAMPLE 15 1 carbobeneoxy 4 cyclohexylcarbamylpiperazine To 88 g. of aniced toluene solution of 0.1 mole ofl-carbobenzoxy-4-chlorocarbonylpiperazine in 250 ml. of ethyl acetate,24.8 g. (0.25 mole) of cyclohexylamine was added, in portions, withshaking. After 2 hours at room temperature, the resulting colorlesscrystals were removed by filtration, washed with ethyl acetate,air-dried and washed with water to remove the cyclohexylaminehydrochloride, yielding 11.8 g. of crude 1 carbobenzoxy 4cyclohexylcarbamylpiperazine. The ethyl acetate mother liquor wasconcentrated to dryness under reduced pressure, yielding an additional25.3 g. of colorless product. When recrystallized from ethyl acetate and60% aqueous ethanol, colorless crystals were obtained, melting point118-119 0.

EXAMPLE 16 1 carbobeneoxy 4 benzylcarbamylm'pGraeme A mixture of 20 g.(0.0785 mole) of phenylacethydroxamic acid benzoate, 45.2 g. (0.205mole) of 1-carbobenzoxypiperazine, and 100 ml. of Water was heated on asteam bath for 10 minutes. The mixture became cloudy and an oilseparated. The mixture was diluted with 225 ml. of water, chilled andacidified with concentrated hydrochloric acid and the resulting nearlycolorless precipitate was removed by filtration and washed with dilutehydrochloric acid. The precipitate was warmed with aqueous sodiumbicarbonate and the cream-colored precipitate was removed by filtration,washed with water and dried at 100 C. The yield of crudel-carbobenzoxylbenzylcarbamylpiperazine was 21 g. (76% of thetheoretical amount). Recrystallization from absolute ethanol gavecolorless crystals, melting point l34-135 C.

EXAMPLE 17 1 carbobcnzoxy 4 thiocarbamylpipemzine A cold solution of10.7 g. (0.11 mole) of potassium thiocyanate in 10 ml. of water wasadded to a cold solution of 25.7 g. (0.1 mole) ofl-carbobenzoxypiperazine hydrochloride in 38 ml. of water. After hoursat room temperature the solution was concentrated under reduced pressureand the residue was diluted with ethyl acetate and filtered to removethe precipitated potassium chloride. The ethyl acetate filtrate wasconcentrated, yielding 17.4 g. (62% of the theoretical amount) ofcolorless crystals of l-carbobenzoxy 4 thiocarbamylpiperazine. Whenrecrystallized from ethyl acetate, colorless crystals were obtained,melting point 83.5-86.0 C.

EXAMPLE 18 1 carbobenzozcy 4 guanylpz'perazine sulfate A mixture of 26.4g. (0.12 mole) of l-carbobenzoxypiperazine 13.9 g. (0.05 mole) of S-methyl isothiourea sulfate and ml. of ethanol was refluxed for 9 hours,at which time the evolution of methyl mercaptan had ceased. The solutionwas concentrated under reduced pressure and the residual glassy resinwas converted to a granular solid by trituration with ether. The solidwas crystallized from absolute ethanol and aqueous ethanol, yielding10.7 g. (35% of the theoretical amount) of colorless crystals of1-carbobenzoxyl-guanylpiperazine sulfate, melting point 227 C. (withdecomposition).

I claim:

1. 1-carbobenzoxy-4=-carbarnylpiperazine.

2. 1 carbobenzoxy 4 methylcarbamylpiperazine.

3. 1 carbobenzoxy 1 ethylcarbamylpiper azine.

l. 1 carbobenzoxy 4 n propylcarbamylpiperazine.

5. 1 carbobenzoxy 1 cyclohexylcarbamylpiperazine.

6. Compounds having the general formula:

in which R is a member of the group consisting of hydrogen and loweralkyl radicals, R is a member of the group consisting of hydrogen, loweralkyl, monocyclic aryl and cyclohexyl radi cals.

7. A l-carbobenzoxy 4 lower alkylcarbamyh piperazine.

LEON GOLDMAN.

No references cited.

6. COMPOUNDS HAVING THE GENERAL FORMULA: